Case series: clinical outcomes of the transthyretin valine-to-isoleucine mutation in a brother-sister pair
Approximately 4% of the African-American population possess a valine-to-isoleucine (V122I) substitution within the transthyretin protein that results in a tendency for a normally tetrameric protein to dissociate into misfolded, monomeric subunits. These misfolded proteins can then accumulate patholo...
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Published in | European heart journal : case reports Vol. 2; no. 4; p. yty108 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
England
Oxford University Press
01.12.2018
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Abstract | Approximately 4% of the African-American population possess a valine-to-isoleucine (V122I) substitution within the transthyretin protein that results in a tendency for a normally tetrameric protein to dissociate into misfolded, monomeric subunits. These misfolded proteins can then accumulate pathologically and cause an autosomal dominant amyloid cardiomyopathy. Homozygous patients are infrequently documented in case reports, and though there are larger studies among heterozygous patients, there is a lack of studies or reports comparing disease within a family.
In this case series, we discuss a 61-year-old African-American male who succumbed to heart failure secondary to cardiac amyloidosis while awaiting orthotopic heart transplantation. We compare his case with that of his sister, a 65-year-old African-American woman with a history of recurrent supraventricular tachycardia requiring radiofrequency ablation, and intermittent chest pain with chronically elevated troponin despite no evidence of coronary artery disease. The sister in question was found to be homozygous for the transthyretin (TTR) V122I mutation with evidence of infiltrative process on cardiac magnetic resonance imaging, while clinical testing verified a heterozygous genotype in the brother. Here, we compare the clinical course and imaging data for the aforementioned brother-sister pair in the context of the amyloidogenic transthyretin V122I gene variant.
Through this familial report, we aim to highlight the variations in expression both within this family and in comparison, to the population. We also hope to emphasize the importance of genetic testing of families at risk for this specific transthyretin variant within the African-American community especially as novel therapies begin to emerge. |
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AbstractList | Approximately 4% of the African-American population possess a valine-to-isoleucine (V122I) substitution within the transthyretin protein that results in a tendency for a normally tetrameric protein to dissociate into misfolded, monomeric subunits. These misfolded proteins can then accumulate pathologically and cause an autosomal dominant amyloid cardiomyopathy. Homozygous patients are infrequently documented in case reports, and though there are larger studies among heterozygous patients, there is a lack of studies or reports comparing disease within a family.
In this case series, we discuss a 61-year-old African-American male who succumbed to heart failure secondary to cardiac amyloidosis while awaiting orthotopic heart transplantation. We compare his case with that of his sister, a 65-year-old African-American woman with a history of recurrent supraventricular tachycardia requiring radiofrequency ablation, and intermittent chest pain with chronically elevated troponin despite no evidence of coronary artery disease. The sister in question was found to be homozygous for the transthyretin (TTR) V122I mutation with evidence of infiltrative process on cardiac magnetic resonance imaging, while clinical testing verified a heterozygous genotype in the brother. Here, we compare the clinical course and imaging data for the aforementioned brother-sister pair in the context of the amyloidogenic transthyretin V122I gene variant.
Through this familial report, we aim to highlight the variations in expression both within this family and in comparison, to the population. We also hope to emphasize the importance of genetic testing of families at risk for this specific transthyretin variant within the African-American community especially as novel therapies begin to emerge. |
Author | Liu, Jar-Yee Gupta, Pritha Sara, Afrida Wang, Jessica Fan, Judith Liu, Jason Y |
AuthorAffiliation | 3 Institute for Precision Health, Geffen School of Medicine, University of California, Los Angeles, CA, USA 1 Department of Medicine, Geffen School of Medicine, University of California, 10833 Le Conte Avenue Los Angeles, CA, USA 2 Clinical and Translational Science Institute, Geffen School of Medicine, University of California, Los Angeles, CA, USA |
AuthorAffiliation_xml | – name: 2 Clinical and Translational Science Institute, Geffen School of Medicine, University of California, Los Angeles, CA, USA – name: 3 Institute for Precision Health, Geffen School of Medicine, University of California, Los Angeles, CA, USA – name: 1 Department of Medicine, Geffen School of Medicine, University of California, 10833 Le Conte Avenue Los Angeles, CA, USA |
Author_xml | – sequence: 1 givenname: Jason Y surname: Liu fullname: Liu, Jason Y organization: Department of Medicine, Geffen School of Medicine, University of California, 10833 Le Conte Avenue Los Angeles, CA, USA – sequence: 2 givenname: Afrida surname: Sara fullname: Sara, Afrida organization: Clinical and Translational Science Institute, Geffen School of Medicine, University of California, Los Angeles, CA, USA – sequence: 3 givenname: Jar-Yee surname: Liu fullname: Liu, Jar-Yee organization: Clinical and Translational Science Institute, Geffen School of Medicine, University of California, Los Angeles, CA, USA – sequence: 4 givenname: Judith surname: Fan fullname: Fan, Judith organization: Institute for Precision Health, Geffen School of Medicine, University of California, Los Angeles, CA, USA – sequence: 5 givenname: Pritha surname: Gupta fullname: Gupta, Pritha organization: Department of Medicine, Geffen School of Medicine, University of California, 10833 Le Conte Avenue Los Angeles, CA, USA – sequence: 6 givenname: Jessica surname: Wang fullname: Wang, Jessica organization: Department of Medicine, Geffen School of Medicine, University of California, 10833 Le Conte Avenue Los Angeles, CA, USA |
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Cites_doi | 10.1073/pnas.0501609102 10.1074/jbc.M408053200 10.1056/NEJMoa1716153 10.1073/pnas.261419998 10.1186/s12883-017-0948-5 10.1056/NEJMoa1404852 10.1007/s10741-014-9462-7 10.1073/pnas.1121005109 10.3109/13506129.2015.1051219 10.1016/j.jmoldx.2013.08.001 |
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Copyright | The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Cardiology. 2018 |
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Keywords | Amyloid cardiomyopathy Transthyretin cardiomyopathy Case series Homozygous transthyretin V122I Heterozygous transthyretin V122I |
Language | English |
License | This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
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References | Maurer ( key 2019032003033046200_yty108-B10) 2018 Quarta ( key 2019032003033046200_yty108-B3) 2015; 372 Reddi ( key 2019032003033046200_yty108-B4) 2014; 16 Green ( key 2019032003033046200_yty108-B6) 2005; 102 Morais-de-Sa ( key 2019032003033046200_yty108-B5) 2004; 279 Castano ( key 2019032003033046200_yty108-B7) 2015; 20 Bulawa ( key 2019032003033046200_yty108-B9) 2012; 109 Jacobson ( key 2019032003033046200_yty108-B1) 2015; 22 Adams ( key 2019032003033046200_yty108-B8) 2017; 17 Jiang ( key 2019032003033046200_yty108-B2) 2001; 98 Adams ( key 2019032003033046200_yty108-B11) 2018; 379 |
References_xml | – volume: 102 start-page: 14545 year: 2005 ident: key 2019032003033046200_yty108-B6 article-title: Genistein, a natural product from soy, is a potent inhibitor of transthyretin amyloidosis publication-title: Proc Natl Acad Sci USA doi: 10.1073/pnas.0501609102 contributor: fullname: Green – volume: 279 start-page: 53483 year: 2004 ident: key 2019032003033046200_yty108-B5 article-title: The crystal structure of transthyretin in complex with diethylstilbestrol: a promising template for the design of amyloid inhibitors publication-title: J Biol Chem doi: 10.1074/jbc.M408053200 contributor: fullname: Morais-de-Sa – volume: 379 start-page: 11 year: 2018 ident: key 2019032003033046200_yty108-B11 article-title: Patisiran, an RNAi therapeutic for hereditary transthyretin amyloidosis publication-title: N Engl J Med doi: 10.1056/NEJMoa1716153 contributor: fullname: Adams – volume: 98 start-page: 14943 year: 2001 ident: key 2019032003033046200_yty108-B2 article-title: The V122I cardiomyopathy variant of transthyretin increases the velocity of rate-limiting tetramer dissociation, resulting in accelerated amyloidosis publication-title: Proc Natl Acad Sci USA doi: 10.1073/pnas.261419998 contributor: fullname: Jiang – start-page: 1007 volume-title: N Engl J Med year: 2018 ident: key 2019032003033046200_yty108-B10 article-title: Tafamadis treatment for patients with transthyretin amyloid cardiomyopathy contributor: fullname: Maurer – volume: 17 start-page: 181. year: 2017 ident: key 2019032003033046200_yty108-B8 article-title: Trial design and rationale for APOLLO, a Phase 3, placebo-controlled study of patisiran in patients with hereditary ATTR amyloidosis with polyneuropathy publication-title: BMC Neurol doi: 10.1186/s12883-017-0948-5 contributor: fullname: Adams – volume: 372 start-page: 21 year: 2015 ident: key 2019032003033046200_yty108-B3 article-title: The amyloidogenic V122I transthyretin variant in elderly black Americans publication-title: N Engl J Med doi: 10.1056/NEJMoa1404852 contributor: fullname: Quarta – volume: 20 start-page: 163 year: 2015 ident: key 2019032003033046200_yty108-B7 article-title: Natural history and therapy of TTR-cardiac amyloidosis: emerging disease-modifying therapies from organ transplantation to stabilizer and silencer drugs publication-title: Heart Fail Rev doi: 10.1007/s10741-014-9462-7 contributor: fullname: Castano – volume: 109 start-page: 9629 year: 2012 ident: key 2019032003033046200_yty108-B9 article-title: Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade publication-title: Proc Natl Acad Sci USA doi: 10.1073/pnas.1121005109 contributor: fullname: Bulawa – volume: 22 start-page: 171 year: 2015 ident: key 2019032003033046200_yty108-B1 article-title: Prevalence of the amyloidogenic transthyretin (TTR) V122I allele in 14 333 African-Americans publication-title: Amyloid doi: 10.3109/13506129.2015.1051219 contributor: fullname: Jacobson – volume: 16 start-page: 68 year: 2014 ident: key 2019032003033046200_yty108-B4 article-title: Homozygosity for the V122I mutation in transthyretin is associated with earlier onset of cardiac amyloidosis in the African American population in the seventh decade of life publication-title: J Mol Diagn doi: 10.1016/j.jmoldx.2013.08.001 contributor: fullname: Reddi |
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Title | Case series: clinical outcomes of the transthyretin valine-to-isoleucine mutation in a brother-sister pair |
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